Therapy for proliferative disorders such as cancer has advanced significantly. Many proliferative disorders can now be effectively treated by administering therapeutic agents that include natural products, derivatives of natural products and synthetic compounds. Therapy for proliferative disorders, particularly cancer chemotherapy, may comprise administration of a combination of agents.
I. Anthracycline Cancer Chemotherapeutic Agents
The anthracyclines are a well known class of chemotherapeutic compounds that are useful for the treatment of a range of cancers. The class also includes investigational chemotherapeutic agents that are believed likely to be useful for the treatment of cancer. The prototypical anthracyclines were polyketide natural products from Streptomyces species, whose structure contains an 1,2,3,4-tetrahydronaphthacene-6,11-dione moiety, with an aminoglycoside side chain attached at the 1-position, although the class now also includes synthetic analogues. Examples of the anthracyclines include: doxorubicin, aclarubicin, amrubicin, carubicin, daunorubicin, epirubicin, esorubicin, idarubicin, iododoxorubicin, mitoxantrone, pirarubicin, valrubicin, and zorubicin. Those which are currently approved by the United States Food and Drug Administration (FDA) for use in cancer treatment include: doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin. The use of the agents, as with many chemotherapeutic agents, is limited by their toxicity. The toxic effects of anthracycline chemotherapeutic agents include myelosuppression, alopecia, diarrhea, nausea, and vomiting. One of the most serious and limiting toxic effects of anthracyclines is cardiac toxicity, which may be manifested years after treatment with the drug in symptoms such as clinical heart failure. The effect toxic is believed to cumulative, and therefore the total dose that can be given to a patient is limited. For example, for doxorubicin, the most widely used member of the class, it is believed that the maximum lifetime cumulative dose that can be safely given is about 400 to 450 mg/m2.
Doxorubicin
Doxorubicin, an anthracycline antibiotic isolated from Streptomyces peucetius var caesius, is therapeutically useful in the treatment of a broad range of cancers. See South African patent 68,02378 and U.S. Pat. No. 3,590,028, the entire disclosures of which are incorporated herein by reference. The structure of doxorubicin is as shown in Scheme 1 below.

Proliferative disorders for which doxorubicin is administered include acute lymphocytic (lymphoblastic) leukemia; acute non-lymphocytic (myeloblastic) leukemia; breast carcinoma; gastric carcinoma; small cell lung carcinoma; ovarian carcinoma; epithelial carcinoma; thyroid carcinoma; neuroblastoma; Wilm's tumor; transitional bladder cell carcinoma; chronic lymphocytic leukemia; cervical carcinoma; endometrial carcinoma; head and neck carcinoma; primary hepatocellular carcinoma; non-small cell lung carcinoma; pancreatic carcinoma; hepatoblastoma; thymoma; ovarian germ cell tumors; trophoblastic gestational tumors; prostate carcinoma; Hodgkin's lymphoma; non-Hodgkin's lymphoma; Ewing's sarcoma; acquired immunodeficiency syndrome (aids)-associated Kaposi's sarcoma; osteosarcoma; soft tissue sarcoma; multiple myeloma; adrenocortical carcinoma; advanced carcinoid tumors; inoperable esophageal carcinoma; and retinoblastoma.
II. Platinum-Based Cancer Chemotherapeutic Agents
The platins are a well known class of chemotherapeutic compounds (also called platinum-based chemotherapeutic compounds) that are useful for the treatment of proliferative disorders, particularly cancers. The class also includes investigational chemotherapeutic agents that are believed likely to be useful for the treatment of such proliferative diseases. Chemically, the platins are platinum (II) or platinum (IV) complexes which usually conform to the general structure cis-[PtX2(Am)2] or cis-[PtX2Y2(Am)2], where X is an anionic leaving group, Am is an inert amine with at least one NH moiety, X and Am are in a square planar configuration about the platinum, cis denoting that the two X ligands are in a cis configuration relative to each other, and Y is another ligand. The two inert amines in the complex may be distinct ligands or part of single chelating diamine ligand. Similarly the two leaving groups X may be distinct ligands (e.g. chloride) or part of a single chelating ligand (e.g. oxalate). See E. Wong and C. M. Giandomenico, Chem. Rev., 1999, 99, 2451-66, the entire disclosure of which is incorporated herein by reference. These general structures are depicted in Scheme 2 below. Examples of the platins include: cisplatin, carboplatin, oxaliplatin, iproplatin, lobaplatin, picoplatin, satraplatin, spiroplatin, tetraplatin, and zeniplatin. The platins which are currently approved by the FDA for use in cancer treatment include: cisplatin, carboplatin, and oxaliplatin.
The use of the platins, as with many chemotherapeutic agents, is limited by their toxicity. The toxic effects of platins include myelosuppression, peripheral neuropathy, alopecia, diarrhea, nausea, and vomiting. One of the most serious and limiting toxic effects of the platins, particularly cisplatin, is nephrotoxicity. With cisplatin, renal toxicity is observed in about 30% of patients given a 50 mg/m2 dose, and the renal toxicity becomes more prolonged and severe with repeated doses of the drug.
Oxaliplatin
Oxaliplatin is an alkylating agent useful in the treatment of proliferative disorders. See, U.S. Pat. Nos. 5,290,961, 5,338,874 and 5,420,319, the entire disclosures of which are incorporated herein by reference. Proliferative disorders for which oxaliplatin is administered include advanced carcinoma of the colon or rectum. Oxaliplatin antiproliferative activity has also been studied in hepatocellular carcinoma (Becouarn et al., Crit. Rev. Oncol. Hematol., 2001, 40(3), 265-72; and Caussanel et al., J. Natl. Cancer Inst., 1990, 82(12), 1046-50); breast cancer (Cottu et al., Proc. Am. Soc. Clin. Oncol., 2000, 19, 155a); gastric cancer (Louvet et al., Proc. Am. Soc. Clin. Oncol., 2000, 19, 265a); germ cell cancer (Soulie et al., J. Cancer Res., Clin. Oncol., 1999, 125(12), 707-11); head and neck cancer (Degardin et al., Eur. J. Cancer Part B, Oral Oncol., 1996, 32B(4), 278-79); non-small cell lung cancer (Monnet et al., Eur. J. Cancer, 1998, 34(7), 1124-27); non-Hodgkin's lymphoma (Germann et al., Ann. Oncol., 1999, 10(3), 351-54); mesothelioma (Fizazi et al., Proc. Am. Soc. Clin. Oncol., 2000, 19, 578a); ovarian cancer (Piccart et al., J. Clin. Oncol., 2000, 18(6), 1193-202); pancreatic cancer (Rougier et al., Proc. Am. Soc. Clin. Oncol., 2000, 19, 262a); and prostate cancer (Droz et al., Proc. Am. Soc. Clin. Oncol., 2000, 19, 359a (meeting abstract 1415)). The entire disclosures of the above references are incorporated herein by reference.
The structure of oxaliplatin is shown in Scheme 3 below.

Numerous advances have been made in the treatment of proliferative disorders such as cancer. However, new therapies are needed which are capable of treating proliferative disorders.
Because of the toxicity and side effects shown by the above-mentioned chemotherapeutic agents, the need exists for new therapies in the treatment of proliferative diseases, particularly therapies which that have greater potency, lower toxicity and/or activity across a broader spectrum of cell types. One solution would be a composition containing, or method of using the above-mentioned therapeutic agents, wherein the efficacy is improved, for example by a synergistic combination with another compound. Such compositions or methods could be very valuable in the treatment of proliferative diseases. Using such compositions or methods in the treatment of proliferative diseases could provide greater efficacy, or potency, resulting in improved therapeutic response, diminished side effects, or both, as compared to using the above-mentioned chemotherapeutic agents alone.